This systematic review with meta-analysis was conducted to investigate the effect of exercise-based CR programmes on endothelial function (i.e., FMD), as well as to assess the influence of the aerobic exercise method (i.e., HIIT vs. MIT) and exercise modality (i.e., resistance exercise/combined exercise vs. aerobic exercise) on the improvement of endothelial function in patients with HF. Additionally, the effect of exercise-based CR on vascular smooth muscle function (i.e., NMD) was also investigated. Our main finding showed that exercise-based CR programmes enhance FMD in patients with HF, supporting the idea that exercise training is a non-pharmacological therapy capable of restoring endothelial function in these patients. Moreover, HIIT enhances endothelial function to a greater extent than MIT. In contrast, no difference was found between resistance exercise (alone or combined with aerobic exercise) and aerobic exercise for enhancing FMD in patients with HF. On the other hand, we have found that exercise-based CR did not enhance vascular smooth muscle function in patients with HF. Finally, we had insufficient data to study the influence of the aerobic exercise method or exercise modality on the improvement of NMD.
Training-induced effect on endothelial function
In accordance with our hypothesis, we found that exercise-based CR is a non-pharmacological treatment for enhancing endothelial function in patients with HF. Nonetheless, most of the pooled studies performed an aerobic-based CR programme, and only one group (one analysis unit) carried out resistance exercise (55). Therefore, our finding should be restricted to the effect of aerobic exercise on endothelial function. Several mechanisms have been used to explain the effect of aerobic exercise on endothelial function in patients with HF. First, aerobic exercise-induced shear stress increases NO availability (60–62) by inducing endothelial NO synthase phosphorylation (63). Additionally, exercise training promotes vascular healing and neovascularisation by inducing endothelial progenitor cells mobilisation from the bone marrow to the circulation (64–66), which is mediated by pro-angiogenic factors such as chemokines (e.g., stromal cell derived factor 1 alpha), growth factors (e.g., vascular endothelial growth factors), and cytokines (i.e., interleukin-8) (67). Finally, exercise training also increases endothelium-reparative capacity by enhancing intracellular signalling (68).
Our results showed an increase of 2.74% (95% CI = 1.69, 3.79%) in relative FMD after an aerobic-based CR programme compared to non-exercise. We also found an improvement in endothelial function when we used absolute FMD values (0.10 mm [95% CI = 0.05, 0.15 mm]). This data is in line with previous systematic reviews and meta-analyses of patients with HF (69). For instance, Pearson and Smart (21) showed a statistically significant increase in relative FMD after moderate- and vigorous-intensity aerobic exercise (1.00 [95% CI = 0.19, 1.80], and 1.21 [95% CI = 0.60, 1.82], respectively). Moreover, Pearson and Smart (20), who also included other types of intervention (i.e., yoga, pilates, tai chi, hydrotherapy, functional electrical stimulation, and inspiratory muscle training), also found an increase in both relative FMD (1.05 [95% CI = 0.64, 1.46]) and absolute FMD values (0.98 [95% CI = 0.48, 1.48]). However, they used the standardised mean difference as the ES index, which does not allow us to compare the magnitude of their findings with our own. By contrast, we decided to use a non-standardised ES index because it is easier to interpret from a clinical standpoint. In this regard, there is evidence showing that for every 1% increase of FMD there is a cardiovascular risk reduction of 8–13% (70, 71), highlighting the clinical relevance of exercise-induced endothelial adaptations.
On the other hand, previous systematic reviews and meta-analyses have demonstrated that exercise also increases endothelial function in other populations (72–74). Once again, the majority of studies included performed aerobic exercise. For instance, Ashor et al. (23) reported a FMD increase of 2.79% (95% CI = 2.12, 3.45%) in favour of aerobic exercise compared to non-exercise groups in patients suffering from various diseases (e.g., HF, coronary artery disease [CAD], overweight, and peripheral artery disease). Additionally, Manresa-Rocamora et al. (75) reported a FMD improvement of 3.62% (95% CI = 2.62, 4.62%) in favour of exercise-based CR in patients with CAD, while Qiu et al. (76) found a FMD increase of 1.77% (95% CI = 0.94, 2.59%) in patients with type 2 diabetes. The lower training-induced effect on endothelial function in patients with diabetes could be due to the reduced ability of the endothelium of these patients to produce NO as a consequence of hyperglycaemia (77). Overall, these findings support the use of aerobic exercise for improving endothelial function and diminishing mortality in healthy individuals and patients suffering from a wide range of pathologies.
Regarding the degree of heterogeneity of the studies we included, our pooled analysis showed high inconsistency of the results which coincides with the conclusions of previous meta-analyses (20, 23, 75). Therefore, it was necessary to analyse the influence of potential moderator variables on the effect of exercise on FMD in patients with HF. Concerning LVEF, our findings showed an enhancement of FMD of 3.09% (95% CI = 2.01, 4.17%) in patients with HFrEF (i.e., LVEF < 50%) but we found no improvement in patients with HFpEF (i.e., LVEF ≥ 50%). Nonetheless, we only included two studies (three analysis units) which enrolled patients with HFpEF (49, 55). Pearson and Smart (20) also included two studies performed with these patients in their meta-analysis (49, 78). Although subgroup analysis was not performed due to the small number of studies included, their results showed a slight increase of the improvement of FMD after removing both studies. Moreover, only Karavidas et al. (78) evidenced an improvement in endothelial function in patients with HFpEF, but they used functional electrical stimulation instead of exercise as the intervention. The fact that patients with worse prognosis (e.g., patients with HFrEF) seem to benefit more from exercise or have higher training-induced adaptations has been previously reported in the literature (79, 80).
Moreover, differences in pathological mechanisms between HFrEF and HFpEF could explain the opposing effect of exercise on endothelial function based on LVEF (6). Exercise capacity, as measured by VO2 peak depends on cardiac factors (cardiac output) and peripheral factors (arteriovenous oxygen difference that in turn relies on arterial and skeletal muscle function) (8). Patients with HF have arterial functional impairments that include increased stiffness, reduced responsiveness to vasodilatory stimuli, and reduced microvascular perfusion. The contribution of each of these three factors to exercise intolerance varies between HFrEF and HFpEF. Patients with HFrEF have reduced endothelial function (8). On the contrary, previous studies have reported both normal and diminished endothelial function in patients with HFpEF compared to age-matched patients without HF (81–83). Therefore, endothelial disfunction does not seem to contribute to exercise intolerance in HFpEF and the majority of the improvement in VO2 peak with exercise training in these patients is due to enhanced peripheral function (specially microvascular function) but not from improved FMD (49, 84). This could partially explain the small improvement of FMD observed after training in patients with HFpEF compared to HFrEF. Due to the limited number of studies performed with HFpEF patients, further research is required to explain the training-induced effect on endothelial function in this population and limits the scope of our conclusions to patients with HFrEF.
Regarding the artery assessed, all pooled studies carried out measurements of endothelial function in arteries of the upper limbs (i.e., brachial or radial). Our analyses showed a greater improvement of FMD in studies which assessed endothelial function in the radial artery compared to the brachial artery (45, 51, 54). Nonetheless, two of these studies (51, 54) carried out an inpatient exercise-based CR programme and there is evidence that a shorter wait time to exercise-based CR is associated with greater training-induced adaptations (80, 85–87). Therefore, the higher FMD improvement in these studies could be due to a shorter wait time to CR and not to the type of artery assessed.
On the other hand, Benda et al. (43) and Kobayashi et al. (50) carried out a cycle ergometer-based CR programme and assessed both upper- and lower-limb endothelial function. They found that FMD improved in the lower limb arteries (i.e., femoral and tibial arteries) but not on the upper limbs, showing an exercise-induced local effect on the trained limbs. It is noteworthy that most of the studies included in our review carried out lower-limb aerobic exercises (e.g., treadmill, cycle ergometer) (see Table S2). Interestingly, these two studies, which only found improvement in the trained lower-limbs, exercised twice a week (43, 50), while the studies that found enhanced upper-limb endothelial function, trained three or more days a week. These findings show that a low training frequency (e.g., two sessions a week) is sufficient to induce endothelial adaptations in the trained limbs, but a higher training frequency (e.g., more than two sessions) is necessary to reach systemic vascular adaptations (e.g., increased brachial FMD) beyond the active muscles. These findings have important implications for exercise prescription in CR programmes. In addition, our heterogeneity analyses showed a greater training-induced effect on FMD in studies which carried out a higher number of training sessions per week (e.g., more than three sessions compared to less than four), regardless of the variable scale (i.e., categorical or continuous). These results are in accordance with those previously reported by Ashor et al. (23), who found that the frequency of resistance exercise was positively associated with the improvement in FMD in healthy adults. However, this aspect had not been previously analysed in patient with HF (20, 21).
Moreover, other heterogeneity sources should be mentioned. Most of the included studies were judged to be of poor or fair quality, which could lead to bias and partially explain the inconsistency of our findings. This also supports the need of further high-quality trials. On the other hand, there is evidence about the influence of patients’ characteristics on the training-induced effect on endothelial function (88, 89). Nonetheless, aggregated information at the trial level was used to perform meta-analyses, and the relationship between patients’ characteristics and treatment effects was not investigated (90). Finally, an important source of heterogeneity is the protocol used for FMD acquisition (91). The recommended post-deflation time to measure FMD is about 180-sec (68) because it is assumed that it coincides with the peak arterial dilation. Nevertheless, this time window varied greatly between studies, and some of them used shorter post-dilation imaging (60 to 90-sec) (40–42, 44, 47, 50, 57), which could limit the estimation of the true peak dilation.
Since exercise training could be considered a “pill” for improving endothelial function in patients with HF, the efficacy of different “dosages” of exercise, in terms of intensity (i.e., HIIT vs. MIT) and exercise modality, should be tested to properly design exercise-based CR programmes. In this regard, our subgroup analysis showed that the enhancement of endothelial function occurred after both types of aerobic exercise: MIT (2.64% [95% CI = 1.58, 3.71%]) and HIIT (3.53% [95% CI = 0.10, 6.96%]) (Table S4). Moreover, we have found that HIIT improved endothelial function to a greater degree than MIT (2.65% [95% CI = 0.98, 4.33%]; Fig. 4), which is in line with our hypothesis. Ramos et al. (92) and Mattioni Maturana et al. (93) had already reported higher HIIT-induced effects on brachial FMD, but they included healthy people and patients with various diseases (e.g., CAD, diabetes, or obesity). Notably, out of all the pooled studies in our meta-analysis, Benda et al. (43) was the only study that did not find any differences between both aerobic exercise methods for enhancing brachial FMD. Nonetheless, lower-limb exercises were performed twice a week, and a higher training frequency could be necessary to reach exercise-induced systemic effects. The underlying mechanisms are not fully understood, but it has been speculated that HIIT could induce higher shear stress than MIT on the blood vessels wall, promoting greater NO bioavailability (94, 95). In this regard, there is evidence showing both increased blood flow and shear stress with increasing exercise intensity (96). Surprisingly, in contrast to our finding and previous evidence, Qiu et al. (76) and Pearson and Smart (21) found no differences between both aerobic exercise methods in patients with diabetes and HF, respectively. However, their findings are controversial because some of the studies included performed exercise regimes that did not meet the necessary intensity requirements to consider them as HIIT (18). Therefore, they did not actually compare HIIT and MIT, rather intermittent versus continuous moderate-intensity training (97). In order to avoid such bias in our review, we carefully evaluated the exercise characteristics (i.e., intensity of effort bouts) of each of the studies included to properly classify them based on the aerobic exercise method and exercise modality. Therefore, to the best of our knowledge, our meta-analysis is the first to provide evidence of the superiority of HIIT for improving endothelial function in patients with HF. Interestingly, previous systematic reviews with meta-analyses have shown that HIIT is more effective than MIT for enhancing cardiorespiratory fitness in patients with HF (24, 98, 99). The higher exercise-induced endothelial adaptations after HIIT compared to MIT could explain in part the greater effect of HIIT on cardiorespiratory fitness in patients with HF.
Finally, we found that the effect of resistance exercise, alone or combined with aerobic exercise, on FMD is not higher than the effect of aerobic exercise. However, only three studies were pooled (38, 52, 55), which limits the scope of this finding. Munch et al. (52) and Turri-Silva et al. (55) found no differences between resistance exercise and aerobic exercise (i.e., MIT and HIIT, respectively) for enhancing endothelial function. In contrast, Anagnostakou et al. (38) found an increase in FMD of 4.66% (95% CI = 1.94, 7.38%) in favour of combined exercise (i.e., HIIT plus resistance exercise) compared to aerobic exercise (i.e., HIIT). In line with this finding, although combined exercise and aerobic exercise were not directly compared, Qiu et al. (76) reported in their meta-analysis higher FMD improvement in patients with type 2 diabetes after combined exercise (2.49% [95% CI = 1.17, 3.81%]) than after aerobic exercise (1.21% [95% CI = 0.23, 2.19%]). On the contrary, Ashor et al. (23) reported that all exercise modalities similarly enhanced endothelial function in patients and healthy individuals. As we can see, there is insufficient evidence in patients with HF to draw solid conclusions about the influence of the exercise modality on the improvement of endothelial function, and the results of previous meta-analyses are controversial. Therefore, future studies should be performed to clarify whether combined exercise is better than aerobic exercise for increasing endothelial function in patients with HF.